Assessment of cerebral drug occupancy in humans using a single PET-scan: A [11C]UCB-J PET study

Abstract

Purpose: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [¹¹C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals.

Methods: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [¹¹C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model.

Results: SV2A occupancies and V_ND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC₅₀), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits.

Conclusion: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC₅₀ values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy.

Clinical trial registration: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search.

Keywords: Displacement; Half maximal inhibitory concentration; Healthy volunteers; Levetiracetam; Occupancy; PET kinetic modeling.

Fig. 1

Levetiracetam plasma concentrations during displacement PET scans. * Individuals scanned twice on the same day. Mg/kg: Levetiracetam dose in milligrams per kilogram body weight. PET: Positron emission tomography

Fig. 2

Levetiracetam plasma concentrations during block PET scans. *: Individuals scanned twice on the same day. Mg/kg: Levetiracetam dose in milligrams per kilogram body weight. PET: Positron emission tomography

Fig. 3

Plasma LEV concentration versus brain SV2A occupancy. Average AUC of plasma LEV concentration (µg/mL) and maximum SV2A occupancy calculated with the Lassen plot, the Numerical solution, and the Single-step solution. LEV: Levetiracetam. SV2A: Synaptic Vesicle Glycoprotein 2 A. AUC: Area under the plasma levetiracetam-time curve. *: Individuals scanned twice on the same day

Fig. 4

Bland-Altman comparisons between the displacement model and the Lassen plot method. Bland-Altman plots between estimated SV2A occupancies for all 11 individuals using the Numerical solution and the Lassen plot (a) and the Single-step solution and the Lassen plot (b). For individuals scanned twice on the same day (c) and on two different days (d) for the Numerical solution and the Lassen plot. For individuals scanned twice on the same day (e) and on two different days (f) for the Single-step solution and the Lassen plot. Note that the occupancy estimates from the displacement model and the Lassen plot do not necessarily correspond to the same LEV exposure. SD: Standard deviation. CV: Coefficient of variation